Smarca4 coordinates chromatin accessibility and metabolic programs to sustain hematopoietic stem cell function

Hematopoietic stem cells (HSCs) sustain lifelong hematopoiesis by balancing quiescence, self-renewal, and differentiation. However, immunophenotypic definitions of HSCs often fail to capture their functional state, particularly under conditions of stress, aging, or disease, where phenotypic HSCs may accumulate despite profound defects in long-term reconstitution. Here, we identify the chromatin remodeling ATPase Smarca4 (BRG1) as a critical regulator of functional HSC integrity. Conditional deletion of Smarca4 in the adult hematopoietic system leads to rapid hematopoietic failure, characterized by an expansion of phenotypically defined HSCs with impaired durable self-renewal capacity. Mechanistically, Smarca4 cooperates with the lineage-associated transcription factor RUNX1 to maintain chromatin accessibility and enhancer activity at the Pparg locus. Loss of Smarca4 selectively disrupts enhancer-associated H3K27ac, rewires metabolic gene programs, and compromises cellular energy homeostasis in HSCs. Restoration of Pparg expression partially rescues metabolic features and early progenitor composition but fails to restore normal differentiation output. Together, our findings establish Smarca4 as an essential epigenetic coordinator that integrates chromatin architecture with metabolic programming to sustain functional hematopoietic stem cell identity.